Patent EA-004628-B1 (EA)
Title: Novel 1,3-dihydro-2h-indol-2-one derivatives and their use as ligands for v1b and v1a arginine-vasopressin receptors
Inventor: ROUX RICHARD
IPC: A61P43/00
Filed: 2001-01-24
Abstract: 1. A compound of formula: in which: R1 represents a halogen atom; a (C1-C4)alkyl; a (C1-C4)alkoxy; a trifluoromethyl radical; a trifluoromethoxy radical; R2 represents a hydrogen atom; a halogen atom; a (C1-C4)alkyl; a (C1-C4)alkoxy; a trifluoromethyl radical; or R2 is in position -6- of the indol-2-one ring and R1 and2 together represent a divalent trimethylene radical; R3 represents a halogen atom; a hydroxyl; a (C1-C2)alkyl; a (C1-C2)alkoxy; a trifluoromethoxy radical; R4 represents a hydrogen atom; a halogen atom; a (C1-C2)alkyl; a (C1-C2)alkoxy; R4 is in position -3- of the phenyl and R3 and R4 together represent a methylenedioxy radical; R5 represents an ethylamino group; a dimethylamino group; an azetidin-1-yl radical; a (C1-C2)alkoxy; R6 represents a hydrogen atom; a (C1-C4)alkyl; a group -(C1-C2)n-CO-R9; a group -CO-(CH2)n-NR10R11; R7 represents a (C1-C4)alkoxy; R8 represents a (C1-C4) (C1-C4)alkoxy; R9 represents a hydroxyl; a (C1-C4)alkoxy; a group -NR12R13; R10 and R11each independently represent a (C1-C4)alkyl; or R10 and R11, together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl or thiomorpholin-4-yl; R12 represents a hydrogen or a (C1-C4)alkyl; R13 represents a (C1-C4); a -C(CH3)2CH2OH group; a -C(CH3)(CH2OH)2 group; a -C(CH2OH)3 group; or R12 and R13, together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl or thiomorpholin-4-yl; n is 1 or 2; or a solvate, hydrate or acid-addition salt thereof. 2. A compound according to claim 1, in the form of optically pure isomers. 3. A compound according to claim 1, of formula: in which: the carbon atom bearing substituent OR6 has the (R) configuration and the carbon atom in position 3 of the indol-2-one has either the (R) configuration or the (S) configuration. 4. A compound according to claim 3, in the form of the levorotatory isomer. 5. A compound according to claim 4 in which: R1 represents a chlorine atom, a methyl radical or a trifluoromethoxy radical; R2 represents a hydrogen atom or is in position -6- of the indol-2-one and represents a chlorine atom, a methyl radical, a methoxy radical or a trifluoromethyl radical; R3 represents a chlorine atom, a fluorine atom, a methoxy radical or an ethoxy radical; R4 represents a hydrogen atom or is in position -3- or -4- of the phenyl and represents a fluorine atom or a methoxy radical; or R4 is in position -3- of the phenyl and, together with R3, represent a methylenedioxy radical; R5 represents a dimethylamino radical or a methoxy radical; R6 represents a hydrogen atom; a methyl radical; an ethyl radical; a tert-butyloxycarbonylmethyl radical; a carboxymethyl radical; a [[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]carbonylmethyl radical; a (1-piperazinyl)carbonylmethyl radical; a (4-morpholinyl)carbonylmethyl radical; a 3-(4-morpholinyl)propanoyl radical; R7 is in position -2- of the phenyl and represents a methoxy radical; R8 represents a methoxy radical; or an acid-addition salt, solvate or hydrate thereof. 6. A compound according to claim 5 selected from the group consisting of: -(2S,4R)-1-[5-Chloro-1-[2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)- 2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[5-Chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3y-1]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[5-Chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-6 -methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidine-carboxamide, levorotatory isomer; -(2S,4R)-1-[5-Chloro-1-[(3,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)- 2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -Methyl (2S,4R)-1-[5-chloro-3-(2-methoxyphenyl)-1-[(3,4-dimethoxyphenyl)sulphonyl] -2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-2-pyrrolidine-carboxylate, levorotatory isomer; -(2S,4R)-1-[5-Methyl-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)- 2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(azetidin-1-ylcarbonyl)-4-hydroxypyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[5-Trifluoromethoxy-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]3-(2methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[3-(2-Chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-5,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[5-Chloro-1-[(2,4-methoxyphenyl)sulphonyl]-3-(2,3-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)- 6-trifluoromethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; (2S,4R)-1-[6-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)- 2-oxo-2,3-dihydro-1H-indol-3-yl]-4-ethoxy-N,N-dimethyl-2-pyrrolidinecarboxamide levorotatory isomer; -(2S,4R)-1-[(5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2,3-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[5,6-Dichloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -Methyl (2S,4R)-1-(5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-2-pyrrolidinecarboxylate, levorotatory isomer; -Methyl (2S,4R)-1-[5-chloro- 1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3- dihydro-1H-indol-3-yl]-4-methoxy-2-pyrrolidine-carboxylate, levorotatory isomer; -(2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxyphenyl)-2 -oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2,3-difluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2,4-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(1,3-benzodioxol-4-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -tert-Butyl 2-[[(3R,5S)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl]oxy]acetate, levorotatory isomer; -2-[[(3R,5S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[dimethylamino)carbonyl]-3-pyrrolidinyl]oxy]acetic acid, levorotatory isomer; -(2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-[2-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-2-oxoethoxy]-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-4-[2-oxo-2-(1-piperazinyl)ethoxy]-2-pyrrolidinecarboxamide, levorotatory isomer; -(2S,4R)-1-[[(2,4-Dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-d ihydro-1H-indol-3-yl]-N,N-dimethyl-4-[2-oxo-2(4-morpholinyl)ethoxy]-2-pyrrolidinecarboxamide, levorotatory isomer; and -(3R,5S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)- 2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[dimethylamino)carbonyl]-3-pyrrolidinyl 3-(4-morpholinyl)propanoate, levorotatory isomer; or the acid-addition salts, solvates or hydrates thereof. 7. Process for preparing compounds of formula (I) according to Claim 1, possible salts thereof with mineral or organic acids and solvates and/or hydrates thereof, characterized in that: a compound of formula: in which R1, R2, R3, R4, R5 and R6 are as defined for a compound of formula (I) in Claim 1, is reacted, in the presence of a base, with a halide of formula: in which R7 and R8 are as defined for a compound of formula (I) in Claim 1 and Hal represents a halogen atom in the presence of the base. 8. Compound of formula: in which: - R1 represents a halogen atom; a (C1-C4)alkyl; a (C1-C4)alkoxy; a trifluoromethyl radical; a trifluoromethoxy radical; - R2 represents a hydrogen atom; a halogen atom; a (C1-C4)alkyl; a (C1-C4)alkoxy; a trifluoromethyl radical; - or R2 is in position -6- of the indol-2-one ring and R1 and R2 together represent a divalent trimethylene radical; - R3 represents a halogen atom; a hydroxyl; a (C1-C4)alkyl; a (C1-C2)alkoxy; a trifluoromethoxy radical; - R4 represents a hydrogen atom; a halogen atom